Pennington based his analysis of the obesity problem on one fundamental premise that he adopted from the research on homeostasis in the 1930s and early 1940s: Because fuel is ultimately used by the cells themselves, the relationship between fuel supply and demand at this cellular level determines both hunger and energy expenditure. The less fuel available to supply the metabolic demands of our cells, the greater the hunger and the less energy we will expend. The greater the fuel available to the cells, the greater the metabolic activity and perhaps physical activity also. This was something Francis Benedict had suggested in the 1920s and Eugene Du Bois believed. Energy expenditure, wrote Pennington, is an “index of calorie nutrition at the cellular level.”

Pennington considered two facts about obesity to be particularly revealing. One was Hugo Rony’s observation that an obese individual will spend much of his life in energy balance—in the “static phase” of obesity, to use Rony’s term—just as the lean do. “His caloric intake, like that of people of normal weight, is dictated by the energy needs of his body,” Pennington wrote. “His appetite, far from being uncontrolled, is precisely and delicately regulated.”

The second fact was that when obese individuals try consciously to eat less—when they go on a low-calorie diet—their metabolism and energy expenditure inevitably decrease, just as they do when lean individuals are semi-starved. Benedict had observed this diet-induced decrease in energy expenditure in his lean subjects in his 1917–18 semi-starvation studies. Frank Evans and Margaret Ohlson had made the same observation of the obese. Pennington believed, as Benedict, the Cornell nutritionist Graham Lusk, and others had suggested, that this was the natural response to a diminished supply of energy. Less energy is available to the cells, and so they expend less. On a calorie-restricted diet, Pennington suggested, the obese and the lean become hungry and lethargic for identical reasons—“their tissues are not receiving enough nutriment.”

This presented a dilemma. That the tissues of the lean are semi-starved by calorie restriction is easy to imagine; they don’t have a lot of excess calories to spare. But why would this happen with the obese, who do? Pennington found his answer in a 1943 article by the Columbia University biochemist DeWitt Stetten, who reported that the rate at which fatty acids were released from the fat deposits of congenitally obese mice was significantly slower than it was in lean mice. Stetten had suggested that obesity in these animals was caused by a suppression of the flow of fat from the adipose tissue back into the circulation and its subsequent use by the tissues for fuel.